The Cpx Inner Membrane Stress Response

Guest, Randi L.; Raivio, Tracy

doi:10.1002/9781119004813.ch99

Cited by 6 publications

(2 citation statements)

References 75 publications

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“…Recent work examining L-form growth in Gram-positive bacteria linked the toxicity of b-lactam treatment to an increase in glycolytic flux resulting in the production of toxic reactive oxygen species by the respiratory chain (Kawai et al, 2019). These results are consistent with previous observations regarding toxic changes in tricarboxylic acid (TCA) cycle activity and respiratory behaviors in Escherichia coli challenged with b-lactams (Belenky et al, 2015;Dwyer et al, 2014;Foti et al, 2012;Kohanski et al, 2007), all of which accompany activation of canonical SOS general stress (Miller et al, 2004) and envelope stress responses (Delhaye et al, 2016;Guest and Raivio, 2016;Kohanski et al, 2008;Laubacher and Ades, 2008). Despite these associations, the mechanistic connections between upstream target-proximal perturbations of b-lactam treatment and downstream metabolic processes remain poorly understood.…”

Section: Introductionsupporting

confidence: 88%

Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality

Lobritz

Andrews

Braff

et al. 2022

Cell Chemical Biology

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b-Lactam antibiotics disrupt the assembly of peptidoglycan (PG) within the bacterial cell wall by inhibiting the enzymatic activity of penicillin-binding proteins (PBPs). It was recently shown that b-lactam treatment initializes a futile cycle of PG synthesis and degradation, highlighting major gaps in our understanding of the lethal effects of PBP inhibition by b-lactam antibiotics. Here, we assess the downstream metabolic consequences of treatment of Escherichia coli with the b-lactam mecillinam and show that lethality from PBP2 inhibition is a specific consequence of toxic metabolic shifts induced by energy demand from multiple catabolic and anabolic processes, including accelerated protein synthesis downstream of PG futile cycling. Resource allocation into these processes is coincident with alterations in ATP synthesis and utilization, as well as a broadly dysregulated cellular redox environment. These results indicate that the disruption of normal anabolic-catabolic homeostasis by PBP inhibition is an essential factor for b-lactam antibiotic lethality.

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Section: Introductionsupporting

confidence: 88%

Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality

Lobritz

Andrews

Braff

et al. 2022

Cell Chemical Biology

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“…In addition to regulation of enterobactin biosynthesis, other processes regulated by the Cpx response could facilitate adaptation to the stress caused by enterobactin accumulation. Activation of the Cpx response increases expression of multidrug efflux pumps in E. coli , V. cholerae , Pseudomonas aeruginosa , and Klebsilla pneumoniae (Tian et al, 2016; Guest and Raivio, 2016b), which could lead to increased efflux of periplasmic enterobactin. Indeed, the Cpx-regulated expression of the VexGH efflux pump, which is required for vibriobactin secretion, supports this hypothesis (Kunkle et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Impaired Efflux of the Siderophore Enterobactin Induces Envelope Stress in Escherichia coli

et al. 2019

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The Cpx response is one of several envelope stress responses that monitor and maintain the integrity of the gram-negative bacterial envelope. While several conditions that are known or predicted to generate misfolded inner membrane proteins activate the Cpx response, the molecular nature of the Cpx inducing cue is not yet known. Studies have demonstrated that mutation of multidrug efflux pumps activates the Cpx response in many gram-negative bacteria. In Vibrio cholerae, pathway activation is due to accumulation of the catechol siderophore vibriobactin. However, the mechanism by which the Cpx response is activated by mutation of efflux pumps in Escherichia coli remains unknown. Here we show that inhibition of efflux by deletion of tolC, the outer membrane channel of several multidrug efflux pumps, activates the Cpx response in E. coli as a result of impaired efflux of the siderophore enterobactin. Enterobactin accumulation in the tolC mutant reduces activity of the nicotinamide adenine dinucleotide (NADH) oxidation arm of the aerobic respiratory chain. However, the Cpx pathway remains active in the tolC mutant when either NADH dehydrogenase I, NADH dehydrogenase II, or cytochrome bo3 is absent. Finally, we show that the Cpx response down-regulates transcription of the enterobactin biosynthesis operon. These results suggest that the Cpx response promotes adaptation to envelope stress in enteric bacteria that are exposed to iron-limited environments, which are rich in envelope-damaging compounds and conditions.

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Increased Synthesis of a Magnesium Transporter MgtA During Recombinant Autotransporter Expression in Escherichia coli

Petrovskaya

Ziganshin

Kryukova

et al. 2021

Appl Biochem Biotechnol

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The Cpx Inner Membrane Stress Response

Cited by 6 publications

References 75 publications

Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality

Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality

Impaired Efflux of the Siderophore Enterobactin Induces Envelope Stress in Escherichia coli

Increased Synthesis of a Magnesium Transporter MgtA During Recombinant Autotransporter Expression in Escherichia coli

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